PROJECT SUMMARY/ABSTRACT Nicotine abuse and addiction represent a substantial burden to public health. Nicotine, an active alkaloid in tobacco, is responsible for addiction to tobacco-containing products such as cigars, cigarettes, and vaporized liquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as the recent surge in popularity of nicotine-containing e-cigarettes, there is a great need for innovative research on the neurobiological underpinnings of nicotine addiction and relapse. In 2009, federal regulation of nicotine content was established by the Family Smoking Prevention and Tobacco Control Act in the United States to reduce addiction to cigarette smoking. Specifically, reduction of nicotine content in tobacco products is a control strategy intended to decrease smoking dependence that reduces nicotine content over time (although not to zero), resulting in gradual reduction of intake and dependence. However, nicotine addiction and relapse rates remain high, and the ability of nicotine reduction strategies to effectively reduce tobacco and nicotine addiction is unknown. Our preliminary results illustrate the utility of an efficient and sensitive behavioral economics (BE) protocol for the examination of elasticity of nicotine demand and nicotine motivation. Importantly, this model utilizes a daily within-session nicotine dose-reduction protocol with conditioned cues associated with different doses of nicotine. These cues can then be used to evaluate cue-induced nicotine seeking to different doses to nicotine, as well as the neurobiological sequelae that occur in nicotine-motivated behavior. Nicotine produces cellular adaptations in brain regions associated with drug reward, such as the nucleus accumbens. However, the neurobehavioral mechanisms underlying nicotine relapse vulnerability are relatively unknown. Nucleus accumbens core (NAcore) glutamatergic mechanisms are involved in nicotine relapse, including rapid, transient increased synaptic strength (measured as increased AMPA currents from medium spiny neurons). In the proposed studies, we will determine if nicotine reduction strategy can inhibit cue-induced nicotine seeking as well as aberrant NAcore synaptic plasticity. In Specific Aim 1, we will examine individual differences in nicotine demand elasticity in male and female rats using an abbreviated BE protocol, and determine the ability of abrupt nicotine reduction to inhibit cue-induced nicotine seeking using a reinstatement paradigm. In Specific Aim 2, we will determine if nicotine reduction can inhibit reinstatement- associated NAcore plasticity. In these ways, the proposed studies will uncover the neurobiological basis of the effects of decreasing nicotine dose, and will identify potential neurobiological targets in glutamate signaling for later manipulation that may increase sensitivity to changes in price and dose and could be beneficial for future regulatory purposes. Through these efforts, we will accomplish our overarching goal of determining efficacy of nicotine reduction to promote nicotine use cessation and reduced relapse vulnerability.